(Adapted from applicant's abstract) Dr. Thomas Parker is an Assistant Professor of Pediatrics and a board-certified Neonatologist at The University of Colorado School of Medicine. During his fellowship training at The University of Colorado, he developed an interest in regulation of the perinatal pulmonary circulation. He has extensive experience in whole animal studies of fetal and neonatal pulmonary blood flow in the lamb and has developed a focused interest in hormonal modulation of the pulmonary circulation. His immediate goals are to learn the theories and practice of molecular biology in order to complement his experience in whole animal studies. His long-term goals are to use both whole animal and molecular techniques to focus on independent investigations of hormonal modulation of fetal pulmonary vascular development. The research environment at the University of Colorado Health Sciences Center is ideally suited to foster Dr. Parker's committee. Dr. Steven H. Abman (mentor) has extensive experience in clinical and animal studies of pulmonary vasoreactivity. Dr. Kurt R. Stenmark's work focuses on pulmonary vascular smooth muscle cell phenotypes and pulmonary hypertension. Dr. Russell V. Anthony is a molecular biologist whose expertise is in the field of placentation and angiogenesis. Drs. Stenmark and Anthony, as well as Drs. Shaul and Le Cras will assist Dr. Parker in applying the molecular biology learned during intensive course work to his studies of the effects of estrogens on the fetal and neonatal pulmonary circulation. Dr. Parker's career development will also be enhanced by his regular interaction with members of the Cardiovascular Pulmonary Research laboratory (CVP) and the Perinatal Research Facility. The research plan proposes to investigate the effects of estrogens on fetal pulmonary angiogenesis and vasoreactivity. In preliminary experiments, Dr. Parker has demonstrated that exogenous estradiol causes a marked vasodilator response in the fetal pulmonary circulation which is sustained for several hours. However, mechanisms underlying this unique effect are unknown. In addition, whether high levels of endogenous estrogens contribute to the development of pulmonary vascular structure and function during late fetal life and thereby prepare the lung for birth is unknown. The research plan proposes to explore these questions through a series of experiments integrating physiologic and molecular approaches. Hemodynamic responses of chronically prepared fetal lambs to exogenous estrogen or a specific estrogen receptor blocker will be measured. Changes in expression of markers of angiogenesis (vascular endothelial growth factor and its receptors) and or regulators of fetal pulmonary vascular tone (the nitric oxide, prostacyclin, and endothelia cascades) will be studied. The proposed research will define the role of endogenous estrogens in pulmonary vascular development and clarify basic mechanisms by which estrogens regulate angiogenesis and vascular tone in the fetal lung.